Compositions comprising hmg-coa reductase inhibitor

ABSTRACT

The present invention relates to pharmaceutical compositions for sustained release comprising as active ingredient an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, said composition comprising an inner phase (internal) and an outer phase (external), wherein at least the outer phase comprises at least one matrix former.

The present invention relates to pharmaceutical compositions forsustained release comprising as active ingredient an HMG-CoA reductaseinhibitor or a pharmaceutically acceptable salt thereof, saidcomposition comprising an inner phase (internal) and an outer phase(external), wherein at least the outer phase comprises at least onematrix former. When using the composition according to the presentinvention, unexpected advantages can be demonstrated.

The term “modified”, “extended” “sustained release” hereinbefore andhereafter shall corresponds to an active ingredient that is releasedfrom the dosage form over an extended period of time, for examplegreater than about four hours. Preferably, the pharmaceuticalcompositions release less than about 80 weight percent of the activeagent in the first eight hours after ingestion of the composition, withthe balance of the pharmaceutically active agent being releasedthereafter. In preferred compositions, less than about 15 weight percentof the pharmaceutically active agent is released in the first 0.5 hourafter ingestion, from about 10 to about 50 weight percent of thepharmaceutically active agent is released within about 2 hours afteringestion, and from about 40 to about 90 preferably about 40 to about 60weight percent of the pharmaceutically active agent is released withinabout 6 hours after ingestion.

HMG-CoA reductase inhibitors, also calledβ-hydroxy-β-methylglutaryl-co-enzyme-A reductase inhibitors (and alsocalled statins) are understood to be those active agents which may bepreferably used to lower the lipid levels including cholesterol in bloodand can be used e.g. for the prevention or treatment of hyperlipidemiaand artheriosclerosis.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features.

HMG-CoA reductase inhibitor compounds are disclosed, e.g., in thefollowing commonly assigned patents, published patent applications andpublications which are all hereby incorporated herein by reference:

Specific examples of compounds disclosed in the above publications,which are HMG-CoA reductase compounds suitable to be employed as thedrug active agent in the compositions of the invention, comprise thefollowing sodium salts, or other pharmaceutically acceptable salts:

-   (E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic    acid, calcium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-dimethylaminopyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[3-(4-fluorophenyl)-spiro[cyclopentane-1,1′-1H-inden]-2′-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-indolizin-2-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-4-oxo-1,4-dihydroquinolin-2-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[3-(1-methylethyl)-5,6-diphenyl-pyridazin-4-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-2-oxo-2,3-dihydroimidazol-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-1-oxo-1,2-dihydro-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-pyrrolo[2,1-a]isoquinolin-2-yl]-3,5-dihydroxy-6-heptenoic    acid sodium salt;-   erythro-(±)-(E)-7-[4-cyclopropyl-6-(4-fluorophenyl)-2-(4-methoxyphenyl)pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-dimethylpyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[(4    (3,5-dimethylphenyl)-6-methyl-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[3,4-bis(4-fluorophenyl)-6-(1-methylethyl)-pyridazin-5-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-5-phenyl-1H-pyrrol-2-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-6-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoic    acid, sodium salt;-   erythro-(±)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoic acid,    sodium salt;-   erythro-(±)-(E)-7-[4-(4-fluorophenyl)-1,2-bis(1-methylethyl)-3-phenylpyrrol-2-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxymethyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(÷)-(E)-[2-(4-fluorophenyl)-4,4,6,6-tetramethyl-cyclohexen-1-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt;-   erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt; and-   erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic    acid, sodium salt.

Preferred are compounds which are selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, nisvastatin,pitavastatin (formerly itavastatin), pravastatin, rosuvastatin, andsimvastatin, or, in each case, a pharmaceutically acceptable saltthereof.

Especially preferred HMG-Co-A reductase inhibitors are those agentswhich have been marketed. Most preferred are atorvastatin, fluvastatin,nisvastatin, pitavastatin or simvastatin or a pharmaceuticallyacceptable salt thereof, in the first line pitavastain or apharmaceutically acceptable salt thereof.

Only salts that are pharmaceutically acceptable and non-toxic are usedtherapeutically and those salts are therefore preferred.

The corresponding active ingredient or a pharmaceutically acceptablesalt thereof may also be used in form of a solvate, such as a hydrate orincluding other solvents, used for crystallization.

The structure of the active agents identified hereinbefore orhereinafter by generic or trade names may be taken from the actualedition of the standard compendium “The Merck Index” or from databases,e.g. Life cycle Patents International (e.g. IMS World Publications). Thecorresponding content thereof is hereby incorporated by reference. Anyperson skilled in the art is fully enabled to identify the active agentand, based on these references, likewise enabled to manufacture and testthe pharmaceutical indications and properties in standard test models,both in vitro and in vivo.

In a preferred embodiment of the present invention the amount of anHMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereofis about 5 to 50% by weight of the dosage unit form, preferably about 5to 20%, most preferably about 10 to 20% of the dosage unit form, e.g.about 10%, e.g. about 11% of the dosage unit form.

In an especially preferred embodiment of the invention the amount of anHMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereofis about 1-32 mg, preferably 1-16 mg per dosage unit form, especiallyfor fluvastatin.

Hydrophilic and/or hydrophobic components can be used as matrix former.

Hydrophilic, non-ionic, slowly swelling and gel forming polymers areemployed as matrix former. These polymers exhibit different swellingcharacteristics and therefore different viscosities in aqueous media andform upon ingestion of the solid dosage form different diffusionbarriers (the matrix) releasing the drug substance by rate-controlleddiffusion of the drug substance through these diffusion barriers. Asubstantial amount of the released active agent may be processedefficiently at the targeted active site. The non-ionic, hydrophilicpolymer is present in an amount providing sufficient strength to the gelmatrix to prevent its premature degradation. The gel matrix should alsobe formed within a time period that is effective to prevent thepremature release of the active agent.

For example, the gel matrix preferably forms within about 5 minutesafter ingestion of the composition to prevent a burst of active agentprior to gel formation. It has turned out that the nonionic, hydrophilicpolymer operates to decrease the rate of gel formation to an acceptablelevel. The non-ionic, hydrophilic polymer may be present in thepharmaceutical composition in an amount ranging from about 1 to about 80weight percent, preferably from about 1 to about 60 weight percent, morepreferably from about 15 to about 50% by weight of the dosage unit form,most preferably from about 18 to about 40% by weight of the dosage unitform.

The matrix former can be selected from the group consisting of ahydroxypropyl methyl cellulose (HPMC), polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, and hydrophilic polymers suchas hydroxypropylcellulose and hydroxymethylcellulose.

The matrix former can furthermore be selected from the group consistingof polysaccharides such as alginate, carrageenan, scleroglucan,pullulan, dextran, haluronic acid, chitin, chitosan and starch.

The matrix former can furthermore be selected from the group consistingof natural polymers such as proteins, for example, albumin or gelatine,and natural rubber.

The matrix former can furthermore be selected from the group consistingof synthetic polymers such as acrylates, for example, polymethacrylate,poly(hydroxy ethyl methacrylate), poly(methyl methacrylate),poly(hydroxy ethyl methacrylate-co-methyl metacrylate, Carbopol 934™,polamides such as polyacrylamide or poly(methylene bis acrylamide),polyanhydrides such as poly(biscarboxyphenoxy)methane, PEO-PPOblock-co-polymers such as poloxamers, polyvinylchloride, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene, polyethylene glycols andco-polymers thereof, polyethylene oxides and co-polymers thereof,polypropylene and co-polymers thereof, polystyrene, polyesters such aspoly(lactic acid), poly(glycolic acid), poly(caprolactone) andco-polymers thereof, poly(ortho esters and co-polymers thereof, resinssuch as Dowex™ or Amberlite™, polycarbonate, cellophane, silicones suchas poly(dimethylsiloxane), polyurethanes, and synthetic rubbers such asstyrene butadiene rubber or isopropene rubber.

The matrix former can furthermore be selected from the group consistingof shellacs, waxes such as carnauba wax, beeswax, glycowax or castorwax, nylon, stearates such as glycerol palmitostearate, glyceroylmonostearate, glyceryl tristearate or stearyl alcohol, lipids such asglycerides or phospholipids, and paraffin.

In a most preferred embodiment of the present invention an HPMC isselected as matrix former.

In a preferred embodiment of the present invention the pharmaceuticalcompositions comprise from about 1 to about 60% of by weight HPMC of thedosage unit form, preferably from about 15 to 50% of by weight HPMC ofthe dosage unit form, more preferably from about 18 to about 40% of byweight HPMC of the dosage unit form.

The HPCM components have an average molecular weight ranging fromapproximately 20'000 to approximately 170'000. These molecular weightsmight correspond to viscosities of approximately 1 to approximately100'000 cps (viscosities values given of 2% aqueous solutions of theHPMC types.).

According to the invention, the matrix former of the internal and/orexternal phase may comprise one or more type(s) of matrix former(s)having different viscosities in each phase.

Preferably, the matrix former of the external phase comprises one ormore type of matrix former component having different viscosities.

In a preferred embodiment of the present invention the matrix former ofthe inner phase has a viscosity of about 1 to about 500 cps, preferablyof about 1 to about 250 cps, more preferably of about 1 to about 125cps.

In a preferred embodiment of the present invention the matrix former ofthe external phase has a viscosity of about 100 to about 100000 cps,preferably of about 100 to 50000 cps, more preferably of about 100 to25000 cps.

Furthermore the invention relates to a corresponding composition,wherein one type of the matrix former component of the external phasehas a viscosity of about 80 to 150 cps and another type of matrix formercomponent has a viscosity of about 50000 to 100000 cps.

In a preferred embodiment the invention the viscosities of the HPMCpolymer(s) used as matrix former in the external phase range fromapproximately 100 to approximately 100'000 cps.

According to the invention, one type of the matrix former component ofthe external phase has a viscosity of approx. 100 cps and the other typeof matrix former component has a viscosity of approx. 100'000 cps.

In a preferred embodiment, the total amount of the matrix forming HPMCcomponent(s) present in the internal phase, having a viscosity of about100 cps ranges from about 0-35 mg, preferably from about 10-35 mg perdosage unit form.

In a preferred embodiment, the total amount of the matrix forming HPMCcomponent(s) present in the external phase, having a viscosity of about100'000 cps ranges from about 10-35 mg per dosage unit form.

In another especially embodiment of the invention, the matrix formingHPMC components are selected from the group consisting of HPMC K100LVPCR 100 cps used in the internal and/or external phase (also namedMethocel K100 Premium LVCR EP (100 cps) and HPMC 100T and HPMC K100LVPCR used in the external phase (also named K100M Premium CR EP (100000cps))

The ratio between HPMC polymers contained in the “internal phase”(granulate) and the external phase, i.e., excipients admixed to thegranulate after the drying/screening process is comprised between 0:100and 100:0, preferably from about 0:50 to about 15:15, e.g 0:30; 0:15;15:15 when comparing the amounts of the components.

The composition according to the present invention furthermore may alsocomprise a stabilizer, especially for protecting the drug substanceadequately against pH-related destabilization.

Additionally, the heat and light sensitivity as well as hygroscopicityof an active ingredient impose particular requirements on themanufacture and storage of pharmaceutical dosage forms.

Certain HMG-CoA reductase inhibitors are extremely susceptible todegradation at pH below about 8. An example of such a compound comprisesthe compound having the USAN designation fluvastatin sodium (hereinafter“fluvastatin”), of the chemical designation:R*,S*-(E)-(±)-7-[3-(4-fluorophenyl)-1-(1-methyl-ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt, [see European Patent Application EP-A-114027].

For example, the degradation kinetics of fluvastatin in aqueous solutionat various pH is illustrated below: % fluvastatin remaining at 37° C. pHafter 1 hour after 24 hrs 7.8 98.3 98.0 6.0 99.6 97.1 4.0 86.7 25.2 1.010.9 0

The above-indicated instability of fluvastatin and related HMG-CoAreductase compounds is believed to be due to the extreme lability of theβ, δ-hydroxy groups on the heptenoic acid chain and the presence of thedouble bond, such that at neutral to acidic pH, the compounds readilyundergo elimination or isomerization or oxidation reactions to formconjugated unsaturated aromatic compounds, as well as the threo isomer,the corresponding lactones, and other degradation products.

In order to achieve marketable dosage forms that meet the internationalquality criteria (e.g. for approval) comprising HMG-CoA reductaseinhibitor compound, it is essential to adequately protect it againstpH-related destabilization by using a stabilizer.

A preferred stabilizer to be used according to the present invention isan “alkaline medium”, said alkaline medium being capable of stabilizingthe composition by imparting a pH of at least 8 to an aqueous solutionor dispersion of the composition. Since the stabilizer is added insolution during the aqueous granulation process, it is in intimatecontact with the active ingredient in the composition to achieve optimalstability of the medicament.

The term “alkaline medium” or “base” employed herein shall refer to oneor more pharmaceutically acceptable substances capable of imparting a pHof at least 8, and preferably at least 9, and up to about pH 10, to anaqueous solution or dispersion of the composition of the invention. Moreparticularly, the alkaline medium creates a “micro-pH” of at least 8around the particles of the composition when water is adsorbed thereonor when water is added in small amounts to the composition. The alkalinemedium should otherwise be inert to the composition compounds. The pHmay be determined by taking a unit dosage of the composition containinge.g. 4 mg of pitavastatin or the equivalent amount of another compoundand dispersing or dissolving the composition in 10 to 100 ml of water.The pharmaceutically acceptable alkaline substance(s) which comprise thealkaline medium may range from water-soluble to sparingly soluble toessentially water-insoluble.

In a preferred embodiment of the present invention, the stabilizer is abasic stabilizer selected from the group consisting of inorganicwater-soluble or inorganic water-insoluble compound.

An inorganic water-soluble compound is a suitable carbonate salt such assodium or potassium carbonate, sodium bicarbonate, potassium hydrogencarbonate, phosphate salts selected from, e.g., anhydrous sodium,potassium or calcium dibasic phosphate, trisodium phosphate, alkalimetal hydroxides, selected from sodium, potassium, or lithium hydroxide,and mixtures thereof.

Sodium bicarbonate advantageously serves to neutralize acidic groups inthe composition in the presence of moisture that may adsorb ontoparticles of the composition during storage.

The calcium carbonate exerts a buffering action in the storedcomposition, without apparent effect on drug release upon ingestion. Ithas further been found that the carbonate salts sufficiently stabilizethe drug substance such that conventional water-based preparativetechniques, e.g. trituration with water or wet granulation, can beutilized to prepare stabilized compositions of the invention.

Examples of water-insoluble compound are suitable alkaline compoundscapable of imparting the requisite basicity include certainpharmaceutically acceptable inorganic compounds commonly employed inantacid compositions (e.g., magnesium oxide, hydroxide or carbonate;magnesium hydrogen carbonate; aluminum or calcium hydroxide orcarbonate; composite aluminum-magnesium compounds, such as magnesiumaluminum hydroxide); as well as pharmaceutically acceptable salts ofphosphoric acid such as tribasic calcium phosphate; and mixturesthereof.

In a preferred embodiment of the invention, the stabilizer is aninorganic water insoluble suitable silicate compound such as magnesiumaluminium silicate (neusilin). Said stabilizer can be introduced in themanufacturing process in the internal phase or in the external phase.Studies showed that neusilin has a higher stabilizing effect than someinorganic water-soluble stabilizers.

The proportion of a particularly stabilizing excipient to be employedwill depend to some extent on the intended manufacturing process. Incompositions to be tableted, for example, calcium carbonate should notexceed a proportion which can no longer be conveniently subjected tocompression, and will generally be used in combination with a morereadily compressible alkaline substance, e.g., sodium bicarbonate. Onthe other hand, capsule dosage forms may comprise higher levels ofpoorly compressible excipients, provided that the overall compositionremains sufficiently free-flowing and processible.

In a preferred embodiment, the amount of the stabilizer is about 1-15weight % of the composition.

In a preferred embodiment, the amount of stabilizer is from about 0.1-10mg per dosage unit.

An example of a stabilized composition according to the invention maycomprise: 0.1 to 60 weight % (wt. %), typically 0.5 to 40 wt. %, of theactive ingredient (e.g., pitavastatin); and preferably 0.1 to 35 wt. %,more preferably 1-15 wt. % (e.g. 1 wt %, 1,25 wt %, 2 wt %, 3 wt %), ofwater insoluble compound such as neusilin or soluble carbonate compound,for example, selected from potassium bicarbonate, potassium carbonateand/or mixtures thereof.

It is a further advantage that the stabilized compositions of theinvention can be readily prepared by aqueous or other solvent-basedtechniques, e.g. wet granulation.

The resulting composition has been found to provide an extended storagelife of the HMG-CoA reductase inhibitor compounds, even in the presenceof moisture or when such compositions additionally comprise otherwisepotentially reactive excipients, such as lactose. The stability of thedrug substance in compositions of the invention can be at least 95%, andis typically between 98% and 99%, after 18 months at 25° C., and foreven longer periods. Compositions also having particularly attractivestorage stability comprise, as an alkaline medium, both a water-solublealkaline excipient and a water-insoluble or sparingly soluble alkalineexcipient.

A solid unit dosage composition may have the ratio of water insoluble tosoluble carbonate carbonate from e.g. 40:1 to 1:2.

An exemplary tablet of the invention may comprise a ratio betweencalcium carbonate and sodium bicarbonate of about 2:1 to 1:2 by weight.A capsule composition may comprise these excipients in a ratio of, forexample, 25:1 to 35:1 by weight.

The composition according to the present invention may furthermorecomprise a filler. In addition to the drug substance and alkalinemedium, a filler is also generally employed in the compositions toimpart processability. Suitable filler materials are well-known to theart (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990),Mack Publishing Co., Easton, Pa., pp. 1635-1636), and includemicrocrystalline cellulose, lactose and other carbohydrates, starch,pregelatinized starch, e.g., starch 1500R (Colorcon Corp.), corn starch,dicalcium phosphate, potassium bicarbonate, sodium bicarbonate,cellulose, calcium phosphate dibasic anhydrous, sugars, sodium chloride,and mixtures thereof, of which lactose, microcrystalline cellulose,pregelatinized starch, and mixtures thereof, are preferred. Owing to itssuperior disintegration and compression properties, microcrystallinecellulose (Avicel PH1, Avicel R, FMC Corp.), and mixtures comprisingmicrocrystalline cellulose and one or more additional fillers, e.g.,pregelatinized starch, are particularly useful. The total filler ispresent in the compositions in an amount of about 1 to 65 wt. %, basedon the total composition, preferably 20 to 60 wt %, more preferably 50wt %. The invention relates to compositions wherein the total amount ofthe filler is from about 20-60 mg, preferably from about 2040 mg perdosage unit and preferably consists of microcrystalline cellulose.

The composition according to the present invention may furthermorecomprise film coating components.

Enteric film coating components may optionally be applied to oraltablets, pellets or capsules to protect against premature degradation ofthe drug substance by gastric acid prior to reaching the intestinalabsorption site. Examples of such materials are well-known and includehydroxypropylmethylcellulose phthalate, cellulose acetate phthalate,polyvinyl acetate phthalate, methylcellulose phthalate, copolymerizedmethacrylic acid/methacrylic acid methyl esters (e.g., EudragitR, RohmPharma). The enteric coating is preferably applied to result in about a5 to 12, preferably 8 to 10, weight percent increase of the capsule,pellet or tablet core. Tableted compositions of the invention aredesirably coated to protect against moisture and light discoloration,and to mask the bitter taste of the drug. Either the enteric coating maycontain opacifiers and colorants, or a conventional opaque film coatingmay be applied to the tablet core, optionally after it has been coatedwith an enteric substance.

Examples of suitable film formers in film coating compositions to beapplied to compositions of the invention comprise, e.g., polyethyleneglycol, polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic polymerssuch as hydroxypropylcellulose, hydroxymethylcellulose, andhydroxypropylmethylcellulose or the like, of whichhydroxypropylmethylcellulose (e.g., Opadry YellowT, Colorcon Corp.) ispreferred. Hydrophobic film-formers which may be applied using anorganic solvent vehicle comprise, for example, ethyl cellulose,cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, etc.

The film coating may be generally applied to achieve a weight increaseof the pellet or core or tablet of about 1 to 10 wt. %, and preferablyabout 2 to 6 wt. %.

Other conventional enteric or film coating composition ingredientsinclude plasticizers, e.g., polyethylene glycol (e.g. polyethyleneglycol 6000), triethylcitrate, diethyl phthalate, propylene glycol,glycerin, butyl phthalate, in conventional amounts, as well as theabove-mentioned opacifiers such as titanium dioxide, and colorants, e.g.iron oxide, aluminum lakes, etc.

The enteric or film coatings can be applied by conventional techniquesin a suitable coating pan or fluidized bed apparatus using water and/orconventional organic solvents (e.g., methyl alcohol, ethyl alcohol,isopropyl alcohol), ketones (acetone, ethylmethyl ketone), chlorinatedhydrocarbons (methylene chloride, dichloroethane), etc.

The composition according to the present invention may furthermorecomprise further components.

Further components which may be incorporated into the compositions tofacilitate processing and/or provide enhanced properties of the productdosage form, are selected from the group consisting of:

-   a) well-known tableting binders (e.g., hydroxypropylmethylcellulose,    starch, starch pregelatinized (starch 1500), gelatin, sugars,    natural and synthetic gums, such as carboxymethylcellulose,    methylcellulose, polyvinylpyrrolidone, low substituted    hydroxypropylcellulose, ethylcellulose, polyvinylacetate,    polyacrylates, gelatin, natural and synthetic gums),    microcrystalline cellulose, and mixtures of the foregoing;-   b) disintegrants (e.g., cross-linked carboxymethyl-cellulose,    croscarmelose, crospovidone, sodium starch glycolate);-   c) lubricants (e.g., magnesium stearate, stearic acid, calcium    stearate, glyceryl behenate, hydrogenated vegetable oil, carnauba    wax and the like);-   d) flow agents (e.g., silicon dioxide, talc, polyethylene oxides);-   e) anti-adherents or glidants (e.g., talc)-   f) sweeteners;-   g) coloring mediums (e.g., iron oxide, aluminum lakes);-   h) flavoring mediums;-   i) antioxidants, etc.

Selection of a particular ingredient or ingredients and the amounts usedwill be readily determinable by one skilled in the art by reference tostandard procedures and practices for preparing tableted or encapsulatedor other dosage forms. In general, an effective amount of a tabletingbinder will comprise about 1 to 10 wt. %, and preferably 1 to 5 wt. %;anti-adherents or glidants, about 1 to 10 wt. %; disintegrants, about 1to 5 wt. %, and lubricants, about 0.1 to 2 wt. %, based on the totalcomposition.

A composition according to the invention comprises (in weight percentbased on the total composition):

-   Drug substance: approx. 5-50 wt % of the formulation; preferably    5-20 wt %, for example 10-20 wt %, e.g. about 10 wt %, e.g. about 11    wt %.-   Matrix former: The amount of HPMC as matrix former is between 1 to    80 wt %, preferably between 15 and 50 wt %, more preferably 18-40 wt    %-   Stabilizer (alkaline medium): 1-15 wt %-   Filler: About 1 to 65 wt %, preferably about 20-60 wt %, more    preferably approx. 50 wt %.

The inner phase of the pharmaceutical composition according to theinvention can comprise the drug substance, a filler, a binder astabilizer, and optionally a matrix former.

The outer phase of the pharmaceutical composition according to theinvention can comprise at least a matrix former agent, a flow agent, alubricant, and optionally a filler.

In a preferred embodiment the drug substance consists in pitavastatinCa-salt. The drug substance is used preferably at about 10%, e.g. 10.45wt % (by weight of the dosage unit form).

In a preferred embodiment the filler consists in microcrystallinecellulose. The total amount of filler is used preferably at about 50% byweight of the dosage unit form. In a most preferred embodiment, thefiller of the internal phase is used at about 20-52 wt % e.g. at about26,05 wt %, about 39,8 wt %, about 44,8 wt %, about 46, 67 wt %, orabout 51,05 wt % (by weight of the dosage unit form). In a mostpreferred embodiment, the filler of the external phase is used at about15-20 wt %, e.g. 18,75 wt %.

In a preferred embodiment the binder consists in low substitutedhydroxypropylcellulose HPC or hydroxypropylmethylcellulose HPMC (e.g. 3or 6 cps). In a preferred embodiment, the binder is used at about 1-10wt %, e.g. 10 wt %, most preferably 1-5 wt %, e.g. at about 3, 125 wt %,or 5 wt %.

In a preferred embodiment the stabilizer consists in potassiumbicarbonate or magnesium aluminium metasilicate (neusilin). In apreferred embodiment the stabilizer is used at about 1-15 wt % by weightof the dosage unit form e.g. at about 1.25 wt %.

In a preferred embodiment the matrix former of the internal phaseconsist in HPMC having a viscosity of about 100 cps and used at about15-40 wt %. In a most preferred embodiment the matrix former of theinternal phase is used at about 18,75 wt %, about 31,25 wt %, or about37,5 wt %, by weight of the dosage unit form.

In a preferred embodiment the matrix former of the external phaseconsist in HPMC. According to the invention, one type of the matrixformer component of the external phase has a viscosity of approx. 100cps and the other type of matrix former component has a viscosity ofapprox. 100'000 cps.

In a most preferred embodiment the matrix former of the external phasehaving a viscosity of approx 100 cps is used at about 15-40 wt %, e.g.at about 18.75 wt % or about 37,5 wt % by weight of the dosage unitform.

In a most preferred embodiment the matrix former of the external phasehaving a viscosity of approx. 100'000 cps is used at about 15-40 wt %,e.g. at about 18.75 wt % or about 37,5 wt % by weight of the dosage unitform.

In a preferred embodiment the flow agent consists in silicon dioxidecolloidal (e.g. Aerosil). In a preferred embodiment the flow agent isused at about 0.1-2 wt %, e.g. 0.5 wt %.

In a preferred embodiment the lubricant consists in magnesium stearate.In a preferred embodiment the lubricant is used at about 0.1-2 wt %,e.g. 0.5 wt %.

According to the invention, there is provided a composition, wherein theratio between the matrix former in the internal and external phase is:

-   a) from about 0:30 to about 15:15, e.g. 0:30; 0:15; 15:15, when    comparing the amount of the components (in mg).-   b) from about 0:38 to about 18,75:18,75, e.g 0:37,5; 0:18,75;    18,75:18,75, when comparing the weight percent of the components.

The present invention relates to compositions wherein the ratio betweenthe total HPMC 100 cps and HPMC 100'000 cps of the outer phase is

-   a) from about 0:30 to about 30:0, e.g. 0:30; 0:15; 15:15; 15:0;    25:0; 30:0, when comparing the amount of the components (in mg).-   b) from about 0:38 to about 38:0, e.g. 0:37,5; 0:18,75; 0:18,75;    18,75:18,75: 18,75:0; 37,5:0, when comparing the weight percent of    the components.

Furthermore the invention relates to a composition wherein the ratiobetween HPMC 100 cps of the internal phase and HPMC 100'000 cps of theexternal phase is:

-   a) from about 0:30 to about 30:0, e.g 0:30; 0:15; 15:15; 15:0; 25:0;    30:0 when comparing the amount of the components (in mg).-   b) from about 0:38 to about 38:0, e.g. 0:37,5; 18,75:18,75; 18,75:0;    31,25:0; 37,5:0 when comparing the weight percent of the components.

The invention particularly relates to compositions wherein the ratiobetween the matrix forming HPMC in the internal phase and the totalweight, is:

-   a) from about 0:80 to about 30:80, e.g. 0:80; 15:80; 25:80; 30:80    when comparing the amount of the components (in mg).-   b) from about 0:100 to about 38:100, e.g. 0:100; 18,75:100;    31,25:100; 37,5:100 when comparing the weight percent of the    components.

The invention particularly relates to compositions wherein the ratiobetween the matrix forming HPMC in the external phase and the totalweight is:

-   a) from about 0 to about 30:80, preferably from about 15:80 to about    30:80, e.g 15:80; 30:80 when comparing the amount of the components    (in mg).-   b) from about 18:100 to a bout 38:100, e.g 18,75:100; 37,5:100 when    comparing the weight percent of the components.

The invention particularly relates to compositons wherein the ratiobetween the total amount of matrix forming HPMC and the total weight,is:

-   a) from about 15:80, to about 30:80 e.g 15:80; 25:80; 30:80; when    comparing the amount of the components (in mg).-   b) from about 18:100 to a bout 38:100, e.g 18,75:100; 37,5:100 when    comparing the weight percent of the components.

The present invention is concerned with compositions wherein the ratiobetween the matrix forming HPMC total and the HMG-CoA reductaseinhibitor is

-   a) from about 15:8,36 to about 30:8,36, e.g 15:8,36; 30:8,36 when    comparing the amount of the components (in mg).-   b) from about 18, 75:10,45 to about 37,5:10,45, e.g 18, 75:10,45;    37,5:10,45 when comparing the weight percent of the components.

According to the invention, there are provided compositions wherein theratio between the matrix forming HPMC in the internal phase and theHMG-CoA reductase inhibitor is

-   a) from about 0 to approx. 6/1, preferably from about 0 to about    30:8, e.g 15:8,36; 25:8,36; 30:8,36 when comparing the amount of the    components (in mg).-   b) from about 0:10,45 to about 38:10.45, e.g. 0:10,45; 18,75:10,45;    31,25:10,45; 37,5:10,45 when comparing the weight percent of the    components.

According to the invention, there are provided compositions wherein theratio between the matrix forming HPMC in the external phase and theHMG-CoA reductase inhibitor is

-   -   a) from about 0 to about 30:8, e.g 15:8,36; 30:8,36 when        comparing the amount of the components (in mg).    -   b) From about 0 to about 37,5:10,45 preferably 18,75:10,45 to        about 37,5:10,45, e.g 18,75:10,45; 37,5:10,45 when comparing the        weight percent of the components.

According to the invention, there is provided a composition, wherein theratio between the matrix former in the internal and external phase is

-   a) from about 0:30 to about 30:0, e.g 0:30; 0:15; 15:15; 25:0; 30:0    when comparing the amount of the components (in mg).-   b) from about 0:38 to about 16:16, e.g 0:37,5; 0:18,75; 18,75:18,75;    31,25:0; 37,5:0 when comparing the weight percent of the components.

Furthermore the invention relates to a composition wherein the ratiobetween the filler in the internal phase and the matrix former HPMCcomprised in the internal phase is

-   -   a) from about 35:0 to about 40:30, e.g. 37,34:0; 35,84:15;        35,80:30; 20,84:15;31,84:15; 33,64:15; 40,84:25 when comparing        the amount of the components (in mg).    -   b) from about 47:0 to about 40:19, e.g. 46,67:0; 44,8:18,75;        44,8:37,5; 42,05:18,75; 51,05:31.25; 26,05:18,75; 39,8:18,75        when comparing the weight percent of the components.

The invention particularly relates to a composition wherein the ratiobetween the total matrix former HPMC in the internal phase and the totalweight, is

-   -   a) from about 0:80 to about 30:80, e.g 0:80; 15:80; 25:80; 30:80        when comparing the amount of the components (in mg).    -   b) from about 0:100 to about 37,5:100, e.g. 0:100; 18,75:100;        31,25:100; 37,5:100 when comparing the weight percent of the        components.

The invention particularly relates to a composition wherein the ratiobetween the total matrix former HPMC in the external phase and the totalweight is

-   -   a) from about 15:80 to about 30:80, e.g, 15:80; 30:80 when        comparing the amount of the components (in mg).    -   b) From about 18,75:100 to about 37,5:100, e.g 0:100; 18,75:100;        37,5:100 when comparing the weight percent of the components.

The invention particularly relates to a composition wherein the ratiobetween the total matrix former HPMC and the total weight is

-   -   a) from about 15:80 to about 30:80, e.g. 15:80; 25:80; 30:80        when comparing the amount of the components (in mg)    -   b) from about 18,75:100 to about 37,5:100, e.g 18,75:100;        31,25:100; 37,5:100 when comparing the weight percent of the        components.

According to the invention, there is provided a composition wherein theratio between the HPMC3 cps intern and the HMG-CoA reductase inhibitoris.

-   -   a) from about 2/9 to about 4/8, e.g 2,5:8,36; 4:8,36 when        comparing the amount of the components (in mg)    -   b) From about 3:10 to about 6:10, e.g 3,125:10,45; 5:10,45 when        comparing the weight percent of the components.

The present invention is concerned with a composition wherein the ratiobetween the HPMC100 cps intern and the HMG-CoA reductase inhibitor is

-   -   a) from about 0:9 to about 30:9, e.g 0:8,36; 15:8,36; 25:8.36;        30:8.36 when comparing the amount of the components (in mg).    -   b) from about 0:10,45 to about 37,5:10.45, e.g 0:10,45;        18,75:10,45; 31,25:10,45; 37,5:10,45 when comparing the weight        percent of the components.

The present invention is concerned with a composition wherein the ratiobetween the matrix former HPMC total and the HMG-CoA reductase inhibitoris:

-   -   a) from about 15:9 to about 30:9, e.g 15:8,36; 25:8,36; 30:8,36        when comparing the amount of the components (in mg).    -   b) from about 18,75:10,45 to about 37,5:10,45, e.g 18,75:10,45;        31,25:10,45; 37,5:10,45 when comparing the weight percent of the        components.

The present invention is concerned with a composition wherein the ratiobetween the filler in the internal phase and the matrix former HPMCcomprised in the internal phase is

-   -   a) from about 37:0 to about 41:25, e.g 37,34:0; 35,84:15;        33,64:15; 20,84:15; 31,84:15; 40,84:25; 35,84:30 when comparing        the amount of the components (in mg).    -   b) from about 46:0 to about 42:19, e.g 46,67:0; 44,8:18,75;        44,8:37,5; 51,05:31,25; 26,05:18,75; 39,8:18,75; 42,05:18,75        when comparing the weight percent of the components.

The invention relates to a composition wherein the ratio between thefiller in the external phase and the matrix former HPMC comprised in theexternal phase is

-   -   a) from about 0:30 to about 15:15, e.g 0:30; 0:15; 15:15 when        comparing the amount of the components (in mg).    -   b) from about 0:37,5 to about 18,75:18,75, e.g 0:37,5; 0:18,75;        18,75:18,75 when comparing the weight percent of the components.

The invention relates to a composition wherein the ratio between thefiller in the internal phase and the matrix former HPMC total is

-   -   a) from about 20:30 to about 38:15, e.g 20,84:30; 31,84:30;        33,64:30; 35,84:30; 37,34:30; 40,84:25; 37,34:15 when comparing        the amount of the components (in mg).    -   b) from about 26:37 to about 47:19, eg. 26,05:37,5; 39,8:37,7;        42,05:37,5; 46,67:37,5; 44,8:37,5; 51,05:31,25; 46,67:18,75 when        comparing the weight percent of the components.

The invention also relates to a composition wherein the ratio betweenthe filler in the external phase and the matrix former HPMC total is

-   a) from about 0:30 to about 15:15, e.g 0:30; 0:25; 15:30; 15:15 when    comparing the amount of the components (in mg).-   b) from about 0:37,5 to about 18,75:18,75, e.g 0:37,5; 0:31,25;    18,75:37,5; 18,75:18,75 when comparing the weight percent of the    components.

It has been surprisingly found that the composition according to theinvention more advantageously increases the distribution of the HMG-CoAreductase inhibitor to the liver due to the slow drug release anddecreases the drug plasma levels and consequently the distribution tothe muscle tissue. The consequence is a better tolerability as comparedto the tolerability of the same dose of an immediate release compositionof the HMG-CoA reductase inhibitor. Because of the improved tolerabilityof the extended release composition higher doses can be administeredleading to higher efficacy of the drug. The improved tolerability of thepharmaceutical composition and consequently higher efficacy, due to thepossibility to administer higher doses, according to the invention isbased on a well adaptated extended release profile. An improved adaptedextended release profile is due notably to the presence of the matrixformer of different viscosities in both the inner and external phase ofthe composition according to the present invention and is also due tothe adequate distribution between the inner and/or outer (external)phase, creating an advantageous diffusion barrier by hydrogel formationof the matrix in aqueous media. Furthermore, a small size of thepharmaceutical dosage form and, in parallel, the possibility to apply alow dose formulation of active ingredient induce a better tolerabilityof the active ingredient.

To obtain very stable compositions, an aqueous or other solvent-basedpreparative process is preferably utilized, whereby the drug substanceand alkaline medium are blended together in the presence of minoramounts of, e.g., water, to provide particles containing the drug andalkaline substance in intimate admixture. The solvent or liquiddispersion medium can be for example, water, ethanol, a polyol (forexample, glycerol, propylene glycol, liquid polyethylene glycols, andthe like), vegetable oils, nontoxic glyceryl esters, and suitablemixtures thereof. Given the hygroscopicity and moisture sensitivity ofHMG-CoA reductase inhibitor compounds such as fluvastatin, it isunexpected that the drug substance is sufficiently stabilized by thealkaline medium to resist degradation by a such techniques.

In another embodiment of a solvent-based process which can assistsubsequent drying in a fluidized bed, the drug substance and alkalinemedium are wet granulated by known techniques, i.e. blended in themoistened state, together with an amount of the filler material. Thethus-formed granules, after drying, are then combined with any remainingfiller and other set-asides, e.g., binder, lubricant, and can thereforebe tableted, encapsulated, or otherwise shaped into a dosage form.Drying is conventionally performed by tray drying or in a fluidized bed,preferably the latter.

It has been found that a water-soluble stabilizing alkaline substancesuch as sodium carbonate or bicarbonate or other alkaline medium, can beadded insitu to the above-described aqueous phase comprising thefluvastatin or other HMG-CoA reductase inhibitor compound, and uponsubjecting this aqueous phase to a freeze-drying procedure, there can beobtained particles comprising the drug compound co-lyophilized with theadded alkaline substance. Very good contacting of the drug andstabilizer can thereby be achieved, to the extent that stablecompositions of the invention may be prepared, for example, from thedrug and sodium carbonate in a weight ratio of about 10/1 to 100/1. Forexample, a co-lyophilized composition of the invention comprising as lowas 0.1% by weight sodium carbonate has been found effective to provide ahighly stabilized drug composition.

As previously indicated, an enteric and/or film coating composition canbe applied to the dosage form for its particular benefits. Enteric orfilm coating of a microcrystalline cellulose-based tablet with awater-based film coating composition is desirably carried out at a bedtemperature of 30-50° C., an inlet temperature of 50-80° C. and arelative humidity (RH) of less than 50%.

The resulting tableted or capsule dosage forms should be protectedduring storage against thermal or light induced oxidation as well asmoisture contamination.

Pharmaceutical compositions, e.g. oral dosage forms, according to theinvention may be formulated in any conventional form, e.g. powders,granules/granulates, capsules or tablets. Preferred pharmaceuticalcompositions may be in the form of tablets.

The pharmaceutical composition according to the invention may have adosage weight from about 5 to about 300 mg, preferably about 100 mg,more preferably about 80 mg.

Such compositions may be formulated by known means to provide standardunitary oral dosages of compound, e.g., 4 mg, 8 mg, 12 mg, 16 mg, etc.,as e.g., powders, granulates, capsules, pellets or tablets.

A special embodiment of the invention relates to tablet having adiameter from 4 to 8 mm, for example from 6 to 8 mm having a weightbetween 70 to 180 mg wherein the active ingredient has a weight between4 and 40 mg per dosage unit form.

Pharmaceutical compositions, e.g. oral dosage forms, hereinabovedescribed may be formed of a granulated mass comprising fluvastatin,HPMC and optionally other exciplents commonly used in pharmaceuticalcomposition, e.g. oral dosage forms, e.g. tablets.

Various dissolution profiles of different strengths can therefore beobtained either by compressing the same tabletting mixture to tablets ofdose proportional weights or by maintaining the same tablet size/weightover all dosage strengths (weight compensation by the excipient used asfiller).

The pharmaceutical compositions according to the invention can beprepared by use of well known pharmaceutical processing techniques suchas blending, granulation, milling, spray drying, compaction, or coating.

-   -   A generic manufacturing procedure of the pharmaceutical        composition, e.g. oral dosage forms can be described in the        following steps:        -   Step 1: Place the drug substance, the matrix former(s) (or            combinations of them), the disintegrant(s) (if requested)            and the filler(s) (if requested, also further components as            listed on page 13) into the bowl of the high shear mixer            (remark: the matrix former may be omitted, according the the            actual composition).        -   Step 2: Mix (e.g., 5 minutes)        -   Step 3: Dissolve the stabilizer in purified water        -   Step 4: Add the solution to the mixture of step (2)        -   Step 5: Rinse the container of step (3) with purified water            and add the rinsing liquid to the mixture of step (4)        -   Step 6: Mix/knead/granulate the compounds.        -   Step 7: Screen the wet granulate (e.g., a sieve of 2 mm mesh            size).        -   Step 8: Dry the granulate on trays or in a fluid bed dryer            (preferred).        -   Step 9: Screen the dried granulate into the container of a            free fall mixer (e.g., a sieve of 1 mm mesh size).        -   Step 10: Mix the matrix former(s), filler(s),            disintegrant(s), glidant(s)/flow agent(s) (if requested,            also further components as listed on page 13) in the free            fall mixer.        -   Step 11: Screen the lubricant(s) to the mixture of step (10)            or prepare a premix of the lubricant(s) with a small part of            the mixture (10) and screen this lubricant(s) premix to the            remaining part of mixture (10).        -   Step 12: Mix the components of step (11).        -   Step 13: Compress the tabletting mixture of step (12) on a            force feeding (rotary) tabletting machine to tablets (or            tablet cores, if film coating is necessary) of the required            weight and dimensions.        -   Step 14: (optional) Add the film formers to the required            liquid (solvents mixtures) or purified water) and dissolve            the film former. Add plasticizer(s), if required.        -   Step 15: (optional) Prepare a suspension of the coloring            agent(s) and titanium dioxide (white pigment) in the            required liquid.        -   Step 16: (optional) Add the suspension of step (15) to the            solution of step (14).        -   Step 17: (optional) Stir the mixture until a homogeneous            dispersion/solution is obtained        -   Step 18: (optional) Spray the suspension of step (17) on the            cores of step (13) until the required weight of the film            coat is achieved.

Said process can be generalized as follow:

-   mixture of components comprising the drug substance and the matrix    former-   addition of a stabilizer-   formation of a granulate-   compression of the granulate to form a tablet or a tablet core-   optional: addition of a film coating comprising a film former    -   In a preferred embodiment, the manufacturing procedure of the        pharmaceutical composition, e.g. oral dosage forms, using        Potassium bicarbonate as stabilizer and HPMC as matrix former        can, for example, be described in the following steps:        -   Step 1: Place the drug substance, HPMC (binder, low            viscosity), HPMC or different HPMC qualities (matrix former,            high viscosity) and microcrystalline cellulose (powder) into            the bowl of the high shear mixer (remark: the matrix former            may be omitted, according the the actual composition).        -   Step 2: Mix (e.g., 5 minutes)        -   Step 3: Dissolve Potassium bicarbonate in purified water        -   Step 4: Add the solution to the mixture (2)        -   Step 5: Rinse the container of step (3) with purified water            and add the rinsing liquid to the mixture of step (4)        -   Step 6: Mix/knead/granulate the compounds.        -   Step 7: Screen the wet granulate (e.g., a sieve of 2 mm mesh            size).        -   Step 8: Dry the granulate on trays or in a fluid bed dryer            (preferred).        -   Step 9: Screen the dried granulate into the container of a            free fall mixer (e.g., a sieve of 1 mm mesh size).        -   Step 10: Mix HPMC or different HPMC qualities (matrix            former, high viscosity), microcrystalline cellulose            (granular) and colloidal silicon dioxide in the free fall            mixer (remark: the microcrystalline cellulose (granular) may            be omitted according to the actual composition).        -   Step 11: Screen magnesium stearate to the mixture of step            (10).        -   Step 12: Mix the components of step (11).        -   Step 13: Compress the tabletting mixture of step (12) on a            force feeding (rotary) tabletting machine to tablets (or            tablet cores, if film coating is necessary) of the required            weight and dimensions.        -   Step 14: (optional) Add the prepared dry powder blend for            the film coat preparation (e.g., Opadry) to purified water        -   Step 15: (optional) Stir the mixture until a homogeneous            dispersion/solution is obtained        -   Step 16: (optional) Spray the suspension of step (15) on the            cores of step (13) until the required weight of the film            coat is achieved.    -   An alternative (generic) manufacturing procedure of the        pharmaceutical composition, e.g. oral dosage forms using        neusilin as stabilizer can be described in the following steps:        -   Step 1: Place the drug substance, the matrix former(s) (or            combinations of them), the disintegrant(s) (if requested),            the Neusilin and the filler(s) (if requested, also further            components as listed on page 13) into the bowl of the high            shear mixer (remark: the matrix former may be omitted,            according the the actual composition).        -   Step 2: Mix (e.g., 5 minutes)        -   Step 3: Add the solution to the mixture of step (2)        -   Step 4: Mix/knead/granulate the compounds.        -   Step 5: Screen the wet granulate (e.g., a sieve of 2 mm mesh            size).        -   Step 6: Dry the granulate on trays or in a fluid bed dryer            (preferred).        -   Step 7: Screen the dried granulate Into the container of a            free fall mixer (e.g., a sieve of 1 mm mesh size).        -   Step 8: Mix the matrix former(s), filler(s),            disintegrant(s), glidant(s)/flow agent(s) (if requested,            also further components as listed on page 13) in the free            fall mixer.        -   Step 9: Screen the lubricant(s) to the mixture of step (8)            or prepare a premix of the lubricant(s) with a small part of            the mixture (9) and screen this lubricant(s) premix to the            remaining part of mixture (8).        -   Step 10: Mix the components of step (9).        -   Step 11: Compress the tabletting mixture of step (10) on a            force feeding (rotary) tabletting machine to tablets (or            tablet cores, if film coating is necessary) of the required            weight and dimensions.        -   Step 12: (optional) Add the film formers to the required            liquid (solvent(s mixtures) or purified water) and dissolve            the film former. Add plasticizer(s), if required.        -   Step 13: (optional) Prepare a suspension of the coloring            agent(s) and titanium dioxide (white pigment) in the            required liquid.        -   Step 14: (optional) Add the suspension of step (13) to the            solution of step (12).        -   Step 15: (optional) Stir the mixture until a homogeneous            dispersion/solution is obtained        -   Step 16: (optional) Spray the suspension of step (15) on the            cores of step (11) until the required weight of the film            coat is achieved.

Said process can be generalized as follow:

-   mixture of components comprising the drug substance the matrix    former and the stabilizer-   formation of a granulate-   compression of the granulate to form a tablet or a tablet core-   optional: addition of a film coating comprising a film former    -   In an other preferred embodiment, the pharmaceutical        compositions according to the invention can be prepared by use        of well known pharmaceutical processing techniques such as        blending, granulation, milling, spray drying, compaction, or        coating, e.g. the manufacturing procedure of the pharmaceutical        composition, e.g. oral dosage forms, using HPMC as matrix former        and neusilin as stabilizer can, for example, be described in the        following steps:        -   Step 1: Place the drug substance, HPMC (binder, low            viscosity), HPMC or different HPMC qualities (matrix former,            high viscosity), microcrystalline cellulose (powder) and            Neusilin into the bowl of the high shear mixer (remark: the            matrix former may be omitted, according to the actual            composition).        -   Step 2: Mix (e.g., 5 minutes)        -   Step 3: Add the granulating liquid to the mixture of step            (2)        -   Step 4: Mix/knead/granulate the compounds.        -   Step 5: Screen the wet granulate (e.g., a sieve of 2 mm mesh            size).        -   Step 6: Dry the granulate on trays or in a fluid bed dryer            (preferred).        -   Step 7: Screen the dried granulate into the container of a            free fall mixer (e.g., a sieve of 1 mm mesh size).        -   Step 8: Mix HPMC or different HPMC qualifies (matrix former,            high viscosity), microcrystalline cellulose (granular) and            colloidal silicon dioxide in the free fall mixer (remark:            the microcrystalline cellulose (granular) may be omitted            according to the actual composition).        -   Step 9: Screen magnesium stearate to the mixture of step            (8).        -   Step 10: Mix the components of step (9).        -   Step 11: Compress the tabletting mixture of step (10) on a            force feeding (rotary) tabletting machine to tablets (or            tablet cores, if film coating is necessary) of the required            weight and dimensions.        -   Step 12: (optional) Add the prepared dry powder blend for            the film coat preparation (e.g., Opadry) to purified water.        -   Step 13: (optional) Stir the mixture until a homogeneous            dispersion/solution is obtained        -   Step 14: (optional) Spray the suspension of step (13) on the            cores of step (11) until the required weight of the film            coat is achieved.

The following examples are intended to illustrate the invention invarious of its embodiments without being limitative in anyway thereof.

EXAMPLE 1

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.67 wt % of microcrystalline cellulose, 3.13 wt % of HPMC (3cps), 1.25 wt % of inorganic water-soluble compound (such as potassiumbicarbonate) or water insoluble compound (such as neusilin), theexternal phase comprising 37.5 wt % HPMC (100'000 cps), 0.5 wt % ofsilicium dioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 1 BIS

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.675 wt % of microcrystalline cellulose, 3.125 wt % of HPMC(3 cps), 1.25 wt % of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 37.5 wt % HPMC (100'000 cps), 0.5 wt % ofsilicium dioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 1 TER

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 37.34 mg of microcrystalline cellulose, 2.5 mg of HPMC (3 cps),1 mg of inorganic water-soluble compound (such as potassium bicarbonate)or water insoluble compound (such as neusilin), the external phasecomprising 30 mg of HPMC (100'000 cps), 0.4 mg of silicium dioxidecolloidal and 0.4 mg of magnesium stearate.

EXAMPLE 2

Inner phase: 10.45 wt % of drug substance-alkaline medium, for examplepitavastatin Ca-salt, 46.67 wt % of microcrystalline cellulose, 3.13 wt% of HPMC (3 cps), 1,25 wt % of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 18.75 wt % HPMC (100'000 cps),18.75 wt % HPMC (100 cps), 0.5 wt % of silicium dioxide colloidal and0.5 wt % of magnesium stearate.

EXAMPLE 2 BIS

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.675 wt % of microcrystalline cellulose, 3.125 wt % of HPMC(3 cps), 1,25 wt % of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 18.75 wt % HPMC (100'000 cps), 18.75 wt %HPMC (100 cps), 0.5 wt % of silicium dioxide colloidal and 0.5 wt % ofmagnesium stearate.

EXAMPLE 2 TER

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 37.34 mg of microcrystalline cellulose, 2.5 mg of HPMC (3 cps),1 mg of inorganic water-soluble compound (such as potassium bicarbonate)or water insoluble compound (such as neusilin), the external phasecomprising 15 mg of HPMC (100'000 cps), 15 mg of HPMC (100 cps), 0.4 mgof silicium dioxide colloidal and 0.4 mg of magnesium stearate.

EXAMPLE 3

Inner phase: 10.45 wt % of drug substance-alkaline medium, for examplepitavastatin Ca-salt, 46.67 wt % of microcrystalline cellulose, 3.13 wt% of HPMC (3 cps), 1,25 wt % of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 37.5% HPMC (100 cps), 0.5 wt %of silicium dioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 3 BIS

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.675 wt % of microcrystalline cellulose, 3.125 wt % of HPMC(3 cps), 1,25 wt % of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 37.5% HPMC (100 cps), 0.5 wt % of siliciumdioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 3 TER

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 37.34 mg of microcrystalline cellulose, 2.5 mg of HPMC (3 cps),1 mg of inorganic water-soluble compound (such as potassium bicarbonate)or water insoluble compound (such as neusilin), the external phasecomprising 30 mg HPMC (100 cps), 0.4 mg of silicium dioxide colloidaland 0.4 mg of magnesium stearate.

EXAMPLE 4

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 44.8 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 18.75 wt % HPMC (100 cps), 1,25 wt % of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 18.75 wt % HPMC(100'000 cps), 0.5 wt % of silicium dioxide colloidal and 0.5 wt % ofmagnesium stearate.

EXAMPLE 4 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 35.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),15 mg of HPMC (100 cps), 1 mg of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 15 mg of HPMC (100'000 cps),0.4 mg of silicium dioxide colloidal and 0.4 mg of magnesium stearate.

EXAMPLE 5

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 44.8 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 37.5 wt % % HPMC (100 cps) 1,25 wt % of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 0.5 wt % of siliciumdioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 5 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 35.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),30 mg of HPMC (100 cps), 1 mg of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 0.4 mg of silicium dioxidecolloidal and 0.4 mg of magnesium stearate.

EXAMPLE 6

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 51.05 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 31.25 wt % HPMC (100 cps) 1,25 wt % of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 0.5 wt % of siliciumdioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 6 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 40.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),25 mg of HPMC (100 cps), 1 mg of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 0.4 mg of silicium dioxidecolloidal and 0.4 mg of magnesium stearate.

EXAMPLE 7

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 26.05 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 18.75 wt % HPMC (100 cps) 1,25 wt of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 18.75 wt % HPMC(100'000 cps), 18.75 wt % of microcrystalline cellulose, 0.5 wt % ofsilicium dioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 7 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 20.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),15 mg of HPMC (100 cps), 1 of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 15 mg of HPMC (100'000 cps), 15 mg ofmicrocrystalline cellulose, 0.4 mg of silicium dioxide colloidal and 0.4mg of magnesium stearate.

EXAMPLE 8

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 26.05 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 18.75 wt % HPMC (100 cps) 1,25 wt % of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 18.75 wt % HPMC (100cps), 18.75 wt % of microcrystalline cellulose, 0.5 wt % of siliciumdioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 8 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 20.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),15 mg HPMC (100 cps) 1 mg of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 15 mg HPMC (100 cps), 15 mg ofmicrocrystalline cellulose, 0.4 mg of silicium dioxide colloidal and 0.4mg of magnesium stearate.

EXAMPLE 9

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 39.8 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 5 wt % of HPC, 18.75 wt % HPMC (100 cps) 1,25 wt % of inorganicwater-soluble compound (such as potassium bicarbonate) or waterinsoluble compound (such as neusilin), the external phase comprising18.75 wt % HPMC (100'000 cps), 0.5 wt % of silicium dioxide colloidaland 0.5 wt % of magnesium stearate.

EXAMPLE 9 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 31.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps), 4mg of HPC, 15 mg of HPMC (100 cps) 1 mg of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 15 mg HPMC (100'000cps), 0.4 mg of silicium dioxide colloidal and 0.4 mg of magnesiumstearate.

EXAMPLE 10

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 39.8 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 5 wt % of HPC, 18.75 wt % HPMC (100 cps), 1,25 wt % of inorganicwater-soluble compound (such as potassium bicarbonate) or waterinsoluble compound (such as neusilin), the external phase comprising18.75 wt % HPMC (100 cps), 0.5 wt % of silicium dioxide colloidal and0.5 wt % of magnesium stearate.

EXAMPLE 10 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 31.84 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps), 4mg of HPC, 15 mg HPMC (100 cps), 1 mg of inorganic water-solublecompound (such as potassium bicarbonate) or water insoluble compound(such as neusilin), the external phase comprising 15 mg HPMC (100 cps),0.4 mg of silicium dioxide colloidal and 0.4 mg of magnesium stearate.

EXAMPLE 11

Inner phase: 10.45 wt % of drug substance-alkaline medium, for examplepitavastatin Ca-salt, 46.67 wt % of microcrystalline cellulose, 3.13 wt% of HPMC (3 cps), 1,25 wt % of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 18.75 wt % HPMC (100'000 cps),18.75 wt % microcrystalline cellulose, 0.5 wt % of silicium dioxidecolloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 11 BIS

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.675 wt % of microcrystalline cellulose, 3.125 wt % of HPMC(3 cps), 1,25 of inorganic water-soluble compound (such as potassiumbicarbonate) or water insoluble compound (such as neusilin) wt %, theexternal phase comprising 18.75 wt % HPMC (100'000 cps), 18.75 wt %microcrystalline cellulose, 0.5 wt % of silicium dioxide colloidal and0.5 wt % of magnesium stearate.

EXAMPLE 11 TER

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 37.34 mg of microcrystalline cellulose, 2.5 mg of HPMC (3 cps),1 mg of inorganic water-soluble compound (such as potassium bicarbonate)or water insoluble compound (such as neusilin), the external phasecomprising 15 mg of HPMC (100'000 cps), 15 mg of microcrystallinecellulose, 0.4 mg of silicium dioxide colloidal and 0.4 mg of magnesiumstearate.

EXAMPLE 12

Inner phase: 10.45 wt % of drug substance-alkaline medium, for examplepitavastatin Ca-salt, 46.67 wt % of microcrystalline cellulose, 3.13 wt% of HPMC (3 cps), 1,25 wt % of inorganic water-soluble compound (suchas potassium bicarbonate) or water insoluble compound (such asneusilin), the external phase comprising 18.75 wt % HPMC (100 cps),18.75 wt % microcrystalline cellulose, 0.5 wt % of silicium dioxidecolloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 12 BIS

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 46.675 wt % of microcrystalline cellulose, 3.125 wt % of HPMC(3 cps), 1,25 wt % of inorganic water-soluble compound (such aspotassium bicarbonate) or water insoluble compound (such as neusilin),the external phase comprising 18.75 wt % HPMC (100 cps), 18.75 wt %microcrystalline cellulose, 0.5 wt % of silicium dioxide colloidal and0.5 wt % of magnesium stearate.

EXAMPLE 12 TER

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 37.37 mg of microcrystalline cellulose, 2.5 mg of HPMC (3 cps),1 mg of inorganic water-soluble compound (such as potassium bicarbonate)or water insoluble compound (such as neusilin), the external phasecomprising 15 mg of HPMC (100 cps), 15 mg of microcrystalline cellulose,0.4 mg of silicium dioxide colloidal and 0.4 mg of magnesium stearate.

EXAMPLE 13

Inner phase: 10.45 wt % of drug substance, for example pitavastatinCa-salt, 42.05 wt % of microcrystalline cellulose, 5 wt % of HPMC (3cps), 18.75 wt % of HPMC (100 cps), 4 wt % of Neusilin, the externalphase comprising 18.75 wt % HPMC (100 000 cps), 0.5 wt % of siliciumdioxide colloidal and 0.5 wt % of magnesium stearate.

EXAMPLE 13 BIS

Inner phase: 8.36 mg of drug substance, for example pitavastatinCa-salt, 33.640 mg of microcrystalline cellulose, 4 mg of HPMC (3 cps),15 mg of HPMC (100 cps), 3.2 mg of Neusilin, the external phasecomprising 15 mg of HPMC (100 000 cps), 0.4 mg of silicium dioxidecolloidal and 0.4 mg of magnesium stearate.

The examples which showed a preferred release profile are examples 1Bis, 2 Bis, 4,7,8,9,11 Bis and 13. Most preferred examples are example 4and example 13.

The present invention also relates to a pharmaceutical composition forthe treatment of hyperlipidemia, hypercholesterolemia andatherosclerosis, as well as other diseases or conditions in whichHMG-CoA reductase is implicated comprising an HMG-CoA reductaseinhibitor or a pharmaceutically acceptable salt thereof and a matrixformer, wherein said composition comprises an internal and an externalphase wherein at least the outer phase comprises a matrix former.

The present invention also relates to a method of treatment ofhyperlipidemia, hypercholesterolemia and atherosclerosis, as well asother diseases or conditions in which HMG-CoA reductase is implicatedcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition according to the invention.

The present invention also concerns a method of releasing apharmaceutically active agent in a mammal, wherein the method includesorally administering the pharmaceutically active agent to the mammal aspart of a composition according to the invention.

The present invention also concerns a pharmaceutical composition for thetreatment of hyperlipidemia, hypercholesterolemia and atherosclerosis,as well as other diseases or conditions in which HMG-CoA reductase isimplicated comprising an HMG-CoA reductase inhibitor or apharmaceutically acceptable salt thereof and a matrix former, whereinsaid composition comprises an internal and an external phase wherein atleast the outer phase comprises a matrix former.

The present invention also concerns the use of the composition accordingto the invention in the manufacture of a medicament for use in thetreatment or prevention of a cardiovascular disease, e.g.,hypercholesterolemia, hyperproteinemia and/or atherosclerosis.

In a preferred embodiment the invention relates to the use of thecomposition according to the invention in the manufacture of amedicament wherein said medicament is a hypercholesteremic,hyperlipoproteinemic or anti-atherosclerotic agent.

1. A pharmaceutical composition for sustained release comprising as active ingredient an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, said composition comprising an inner phase (internal) and an outer phase (external), wherein at least the outer phase comprises at least one matrix former.
 2. A composition according to claim 1, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, or, in each case, a pharmaceutically acceptable salt thereof.
 3. A composition according to claim 2, wherein the HMG-CoA reductase inhibitor is pitavastatin or a pharmaceutically acceptable salt thereof.
 4. A composition according claim 1, wherein the amount of HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof is about 5-50 weight % of the composition.
 5. A composition according to claim 1, wherein the amount of HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof is about 1-32 mg.
 6. A composition according to claim 1, wherein the inner phase comprises a matrix former.
 7. A composition according to claim 6, wherein the matrix former of the inner phase comprises one or more types of matrix former components having different viscosities.
 8. A composition according to claim 7, wherein the matrix former of the inner phase has a viscosity of about 1 to about 500 cps.
 9. A composition according to claim 1, wherein the matrix former of the external phase comprises one or more type of matrix former component having different viscosities.
 10. A composition according to claim 9, wherein the matrix former of the external phase has a viscosity of about 100 to about 100000 cps.
 11. A composition according to claim 1, wherein the matrix former is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic polymers such as hydroxypropylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose or the like.
 12. A composition according to claim 11, wherein the matrix former is hydroxypropylmethylcellulose (HPMC).
 13. A composition according to claim 12 wherein the amount of HPMC as a matrix former is about 1-60 weight % of the composition.
 14. A composition according to claim 1, wherein said composition further comprises a stabilizer.
 15. A composition according to claim 14, wherein the stabilizer is magnesium aluminium metasilicate (neusilin).
 16. A composition according to claim 14, wherein the amount of the stabilizer is about 1-15 weight % of the composition.
 17. A method of treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis, as well as other diseases or conditions in which HMG-CoA reductase is implicated comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to claim
 1. 18. Use of the composition according to claim 1 in the manufacture of a medicament for use in the treatment or prevention of a cardiovascular disease, e.g., hypercholesterolemia, hyperproteinemia and/or atherosclerosis.
 19. A composition according claim 3, wherein the amount of HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof is about 5-50 weight % of the composition
 20. A composition according to claim 3, wherein the amount of HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof is about 5-50 weight % of the composition
 21. A composition according to claim 3, wherein the amount of HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof is about 1-32 mg.
 22. A composition according to claim 3, wherein the inner phase comprises a matrix former
 23. A composition according to claim 3, wherein the matrix former of the external phase comprises one or more type of matrix former component having different viscosities.
 24. A composition according to claim 3, wherein the matrix former is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic polymers such as hydroxypropylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose or the like. 